SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness

Rosalba Carrozzo, Carlo Dionisi-Vici, Ulrike Steuerwald, Simona Lucioli, Federica Deodato, Sivia Di Giandomenico, Enrico Bertini, Barbara Franke, Leo A.J. Kluijtmans, Maria Chiara Meschini, Cristiano Rizzo, Fiorella Piemonte, Richard Rodenburg, René Santer, Filippo M. Santorelli, Arno Van Rooij, Diana Vermunt-De Koning, Eva Morava-Kozicz, Ron A. Wevers

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G → A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1:2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.

Original languageEnglish (US)
Pages (from-to)862-874
Number of pages13
JournalBrain
Volume130
Issue number3
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Fingerprint

Dystonia
Deafness
Mutation
Lactic Acidosis
Methylmalonic Acid
Citric Acid Cycle
Carnitine
Denmark
Mitochondrial DNA
Gene Frequency
Genes
Inborn Errors Metabolism
Methylmalonic acidemia
Caudate Nucleus
Putamen
Homozygote
Body Fluids
Pedigree
Islands
Italy

Keywords

  • Methylmalonic aciduria
  • mtDNA depletion
  • Succinyl-CoA synthetase
  • Succinylcarnitine
  • TCA cycle defect

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Carrozzo, R., Dionisi-Vici, C., Steuerwald, U., Lucioli, S., Deodato, F., Di Giandomenico, S., ... Wevers, R. A. (2007). SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain, 130(3), 862-874. https://doi.org/10.1093/brain/awl389

SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. / Carrozzo, Rosalba; Dionisi-Vici, Carlo; Steuerwald, Ulrike; Lucioli, Simona; Deodato, Federica; Di Giandomenico, Sivia; Bertini, Enrico; Franke, Barbara; Kluijtmans, Leo A.J.; Meschini, Maria Chiara; Rizzo, Cristiano; Piemonte, Fiorella; Rodenburg, Richard; Santer, René; Santorelli, Filippo M.; Van Rooij, Arno; Vermunt-De Koning, Diana; Morava-Kozicz, Eva; Wevers, Ron A.

In: Brain, Vol. 130, No. 3, 01.01.2007, p. 862-874.

Research output: Contribution to journalArticle

Carrozzo, R, Dionisi-Vici, C, Steuerwald, U, Lucioli, S, Deodato, F, Di Giandomenico, S, Bertini, E, Franke, B, Kluijtmans, LAJ, Meschini, MC, Rizzo, C, Piemonte, F, Rodenburg, R, Santer, R, Santorelli, FM, Van Rooij, A, Vermunt-De Koning, D, Morava-Kozicz, E & Wevers, RA 2007, 'SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness', Brain, vol. 130, no. 3, pp. 862-874. https://doi.org/10.1093/brain/awl389
Carrozzo R, Dionisi-Vici C, Steuerwald U, Lucioli S, Deodato F, Di Giandomenico S et al. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain. 2007 Jan 1;130(3):862-874. https://doi.org/10.1093/brain/awl389
Carrozzo, Rosalba ; Dionisi-Vici, Carlo ; Steuerwald, Ulrike ; Lucioli, Simona ; Deodato, Federica ; Di Giandomenico, Sivia ; Bertini, Enrico ; Franke, Barbara ; Kluijtmans, Leo A.J. ; Meschini, Maria Chiara ; Rizzo, Cristiano ; Piemonte, Fiorella ; Rodenburg, Richard ; Santer, René ; Santorelli, Filippo M. ; Van Rooij, Arno ; Vermunt-De Koning, Diana ; Morava-Kozicz, Eva ; Wevers, Ron A. / SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. In: Brain. 2007 ; Vol. 130, No. 3. pp. 862-874.
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abstract = "One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G → A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2{\%}, corresponding with an estimated homozygote frequency of 1:2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.",
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T1 - SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness

AU - Carrozzo, Rosalba

AU - Dionisi-Vici, Carlo

AU - Steuerwald, Ulrike

AU - Lucioli, Simona

AU - Deodato, Federica

AU - Di Giandomenico, Sivia

AU - Bertini, Enrico

AU - Franke, Barbara

AU - Kluijtmans, Leo A.J.

AU - Meschini, Maria Chiara

AU - Rizzo, Cristiano

AU - Piemonte, Fiorella

AU - Rodenburg, Richard

AU - Santer, René

AU - Santorelli, Filippo M.

AU - Van Rooij, Arno

AU - Vermunt-De Koning, Diana

AU - Morava-Kozicz, Eva

AU - Wevers, Ron A.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G → A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1:2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.

AB - One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G → A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1:2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.

KW - Methylmalonic aciduria

KW - mtDNA depletion

KW - Succinyl-CoA synthetase

KW - Succinylcarnitine

KW - TCA cycle defect

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